Predictive factors and early biomarkers of response in multiple sclerosis patients treated with natalizumab

There are an increasing number of treatments available for multiple sclerosis (MS). The early identification of optimal responders to individual treatments is important to achieve individualized therapy. With this aim, we performed a multicenter retrospective longitudinal study including 186 MS patients treated with natalizumab who were followed for 2 years. We analyzed the following variables at recruitment: sex, current age, age at disease onset, disease duration, EDSS, number of T2 and Gd + lesions, IgG and IgM oligoclonal bands, HLA class II (DR, DRB, DQA, DQB, and DRB1*15:01), IgG and IgM antibody titers against human herpesvirus 6 (HHV-6) and the antibody response to Epstein–Barr virus (EBV) through the measurement of the anti-EBNA-1 and anti-VCA IgG titers, in relation to clinical response (no relapses or disability progression), and to NEDA-3 (no evidence of disease activity in terms of clinical response and no changes in MRI scans either) after 2-years follow-up. Baseline EDSS score, baseline EBNA-1 IgG titers and percentage change of HHV6 IgG titers between baseline and 6 month visits were significantly different in clinical responders and in NEDA-3 status (all of them remained significant in the multivariate analysis). We identified three variables for the early identification of natalizumab optimal responders in a rapid and cost-effective approach

Aluminum slurry coatings to replace cadmium for aeronautic applications

Cadmium has been widely used as a coating to provide protection against galvanic corrosion for steels and for its natural lubricity on threaded applications. However, it is a toxic metal and a known carcinogenic agent, which is plated from an aqueous bath containing cyanide salts. For these reasons, the use of cadmium has been banned in Europe for most industrial applications. However, the aerospace industry is still exempt due to the stringent technical and safety requirements associated with aeronautical applications, as an acceptable replacement is yet to be found. Al slurry coatings have been developed as an alternative to replace cadmium coatings. The coatings were deposited on AISI 4340 steel and have been characterized by optical and electron microscopy. Testing included salt fog corrosion exposure, fluid corrosion exposure (immersion), humidity resistance, coating-substrate and paint-coating adhesion, electric conductivity, galvanic corrosion, embrittlement and fatigue. The results indicated that Al slurry coatings are an excellent alternative for Cd replacement

Hospital-based proton therapy implementation during the COVID pandemic: early clinical and research experience in a European academic institution

Introduction A rapid deploy of unexpected early impact of the COVID pandemic in Spain was described in 2020. Oncology practice was revised to facilitate decision-making regarding multimodal therapy for prevalent cancer types amenable to multidisciplinary treatment in which the radiotherapy component searched more efcient options in the setting of the COVID-19 pandemic, minimizing the risks to patients whilst aiming to guarantee cancer outcomes. Methods A novel Proton Beam Therapy (PBT), Unit activity was analyzed in the period of March 2020 to March 2021. Institutional urgent, strict and mandatory clinical care standards for early diagnosis and treatment of COVID-19 infection were stablished in the hospital following national health-authorities’ recommendations. The temporary trends of patients care and research projects proposals were registered. Results 3 out of 14 members of the professional staf involved in the PBR intra-hospital process had a positive test for COVID infection. Also, 4 out of 100 patients had positive tests before initiating PBT, and 7 out of 100 developed positive tests along the weekly mandatory special checkup performed during PBT to all patients. An update of clinical performance at the PBT Unit at CUN Madrid in the initial 500 patients treated with PBT in the period from March 2020 to November 2022 registers a distribution of 131 (26%) pediatric patients, 63 (12%) head and neck cancer and central nervous system neoplasms and 123 (24%) re-irradiation indications. In November 2022, the activity reached a plateau in terms of patients under treatment and the impact of COVID pandemic became sporadic and controlled by minor medical actions. At present, the clinical data are consistent with an academic practice prospectively (NCT05151952). Research projects and scientifc production was adapted to the pandemic evolution and its infuence upon professional time availability. Seven research projects based in public funding were activated in this period and preliminary data on molecular imaging guided proton therapy in brain tumors and post-irradiation patterns of blood biomarkers are reported. Conclusions Hospital-based PBT in European academic institutions was impacted by COVID-19 pandemic, although clinical and research activities were developed and sustained. In the post-pandemic era, the benefts of online learning will shape the future of proton therapy education

PYL8 mediates ABA perception in the root through non-cell-autonomous and ligand-stabilization-based mechanisms

[EN] The phytohormone abscisic acid (ABA) plays a key role regulating root growth, root system architecture, and root adaptive responses, such as hydrotropism. The molecular and cellular mechanisms that regulate the action of core ABA signaling components in roots are not fully understood. ABA is perceived through receptors from the PYR/PYL/RCAR family and PP2C coreceptors. PYL8/RCAR3 plays a nonredundant role in regulating primary and lateral root growth. Here we demonstrate that ABA specifically stabilizes PYL8 compared with other ABA receptors and induces accumulation of PYL8 in root nuclei. This requires ABA perception by PYL8 and leads to diminished ubiquitination of PYL8 in roots. The ABA agonist quinabactin, which promotes root ABA signaling through dimeric receptors, fails to stabilize the monomeric receptor PYL8. Moreover, a PYL8 mutant unable to bind ABA and inhibit PP2C is not stabilized by the ligand, whereas a PYL85KR mutant is more stable than PYL8 at endogenous ABA concentrations. The PYL8 transcript was detected in the epidermis and stele of the root meristem; however, the PYL8 protein was also detected in adjacent tissues. Expression of PYL8 driven by tissue-specific promoters revealed movement to adjacent tissues. Hence both inter- and intracellular trafficking of PYL8 appears to occur in the root apical meristem. Our findings reveal a non-cell-autonomous mechanism for hormone receptors and help explain the nonredundant role of PYL8-mediated root ABA signaling.Work in the P.L.R. and F.M. laboratories was supported by the Ministerio de Ciencia e Innovacion, Fondo Europeo de Desarrollo Regional and Consejo Superior de Investigaciones Cientificas Grants BIO2014-52537-R and BIO2017-82503-R (to P.L.R.) and BIO2015-64307-R (to F.M.). J.L.-J. was supported by a Juan de la Cierva contract from Ministerio de Economia y Competitividad (MINECO) and by the Marie Sklodowska-Curie Action H2020-MSCA-IF-2015-707477. B.B.-P. was funded by Programa VALi+d GVA APOSTD/2017/039. J.J. was supported by a FPI contract from MINECO and M.A.F. by a Formacion de Profesorado Universitario contract from MINECO. D.D. and M.J.B. were supported by Biotechnology and Biological Sciences Research Council Grant BB/M002136/1 and Leverhulme Trust Grant RPG-2016-409.Belda-Palazón, B.; Gonzalez-Garcia, M.; Lozano Juste, J.; Coego Gonzalez, A.; Antoni-Alandes, R.; Julian-Valenzuela, J.; Peirats-Llobet, M.... (2018). PYL8 mediates ABA perception in the root through non-cell-autonomous and ligand-stabilization-based mechanisms. Proceedings of the National Academy of Sciences of the United States of America (Online). 115(50):E11857-E11863. https://doi.org/10.1073/pnas.1815410115SE11857E1186311550Ubeda-Tomás, S., Beemster, G. T. S., & Bennett, M. J. 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Endodermal ABA Signaling Promotes Lateral Root Quiescence during Salt Stress in Arabidopsis Seedlings. The Plant Cell, 25(1), 324-341. doi:10.1105/tpc.112.107227Feng, W., Lindner, H., Robbins, N. E., & Dinneny, J. R. (2016). Growing Out of Stress: The Role of Cell- and Organ-Scale Growth Control in Plant Water-Stress Responses. The Plant Cell, 28(8), 1769-1782. doi:10.1105/tpc.16.00182Geng, Y., Wu, R., Wee, C. W., Xie, F., Wei, X., Chan, P. M. Y., … Dinneny, J. R. (2013). A Spatio-Temporal Understanding of Growth Regulation during the Salt Stress Response in Arabidopsis. The Plant Cell, 25(6), 2132-2154. doi:10.1105/tpc.113.112896Takahashi, N., Goto, N., Okada, K., & Takahashi, H. (2002). Hydrotropism in abscisic acid, wavy, and gravitropic mutants of Arabidopsis thaliana. Planta, 216(2), 203-211. doi:10.1007/s00425-002-0840-3Antoni, R., Gonzalez-Guzman, M., Rodriguez, L., Peirats-Llobet, M., Pizzio, G. A., Fernandez, M. A., … Rodriguez, P. L. (2012). PYRABACTIN RESISTANCE1-LIKE8 Plays an Important Role for the Regulation of Abscisic Acid Signaling in Root. Plant Physiology, 161(2), 931-941. doi:10.1104/pp.112.208678Barberon, M., Vermeer, J. E. M., De Bellis, D., Wang, P., Naseer, S., Andersen, T. G., … Geldner, N. (2016). Adaptation of Root Function by Nutrient-Induced Plasticity of Endodermal Differentiation. Cell, 164(3), 447-459. doi:10.1016/j.cell.2015.12.021Ondzighi-Assoume, C. A., Chakraborty, S., & Harris, J. M. (2016). Environmental Nitrate Stimulates Abscisic Acid Accumulation in Arabidopsis Root Tips by Releasing It from Inactive Stores. The Plant Cell, 28(3), 729-745. doi:10.1105/tpc.15.00946Irigoyen, M. L., Iniesto, E., Rodriguez, L., Puga, M. I., Yanagawa, Y., Pick, E., … Rubio, V. (2014). Targeted Degradation of Abscisic Acid Receptors Is Mediated by the Ubiquitin Ligase Substrate Adaptor DDA1 in Arabidopsis. The Plant Cell, 26(2), 712-728. doi:10.1105/tpc.113.122234Bueso, E., Rodriguez, L., Lorenzo-Orts, L., Gonzalez-Guzman, M., Sayas, E., Muñoz-Bertomeu, J., … Rodriguez, P. L. (2014). The single-subunit RING-type E3 ubiquitin ligase RSL1 targets PYL4 and PYR1 ABA receptors in plasma membrane to modulate abscisic acid signaling. The Plant Journal, 80(6), 1057-1071. doi:10.1111/tpj.12708Knoblich, J. A. (2005). Pins for spines. Nature Cell Biology, 7(12), 1057-1058. doi:10.1038/ncb1205-1057Zhang, H., Han, W., De Smet, I., Talboys, P., Loya, R., Hassan, A., … Wang, M.-H. (2010). ABA promotes quiescence of the quiescent centre and suppresses stem cell differentiation in the Arabidopsis primary root meristem. The Plant Journal, 64(5), 764-774. doi:10.1111/j.1365-313x.2010.04367.xBelda-Palazon, B., Rodriguez, L., Fernandez, M. A., Castillo, M.-C., Anderson, E. M., Gao, C., … Rodriguez, P. L. (2016). 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C., Defries, A., Park, S.-Y., Endo, A., Nambara, E., … Cutler, S. R. (2013). Activation of dimeric ABA receptors elicits guard cell closure, ABA-regulated gene expression, and drought tolerance. Proceedings of the National Academy of Sciences, 110(29), 12132-12137. doi:10.1073/pnas.1305919110Cao, M., Liu, X., Zhang, Y., Xue, X., Zhou, X. E., Melcher, K., … Xu, Y. (2013). An ABA-mimicking ligand that reduces water loss and promotes drought resistance in plants. Cell Research, 23(8), 1043-1054. doi:10.1038/cr.2013.95Castillo, M.-C., Lozano-Juste, J., González-Guzmán, M., Rodriguez, L., Rodriguez, P. L., & León, J. (2015). Inactivation of PYR/PYL/RCAR ABA receptors by tyrosine nitration may enable rapid inhibition of ABA signaling by nitric oxide in plants. Science Signaling, 8(392), ra89-ra89. doi:10.1126/scisignal.aaa7981Wu, S., & Gallagher, K. L. (2014). The movement of the non-cell-autonomous transcription factor, SHORT-ROOT relies on the endomembrane system. The Plant Journal, 80(3), 396-409. doi:10.1111/tpj.12640Nakajima, K., Sena, G., Nawy, T., & Benfey, P. N. (2001). Intercellular movement of the putative transcription factor SHR in root patterning. Nature, 413(6853), 307-311. doi:10.1038/35095061Gallagher, K. L., Paquette, A. J., Nakajima, K., & Benfey, P. N. (2004). Mechanisms Regulating SHORT-ROOT Intercellular Movement. Current Biology, 14(20), 1847-1851. doi:10.1016/j.cub.2004.09.081Pálfy, M., Reményi, A., & Korcsmáros, T. (2012). Endosomal crosstalk: meeting points for signaling pathways. Trends in Cell Biology, 22(9), 447-456. doi:10.1016/j.tcb.2012.06.004Christmann, A., Hoffmann, T., Teplova, I., Grill, E., & Müller, A. (2004). Generation of Active Pools of Abscisic Acid Revealed by In Vivo Imaging of Water-Stressed Arabidopsis. Plant Physiology, 137(1), 209-219. doi:10.1104/pp.104.053082Kim, T.-H., Hauser, F., Ha, T., Xue, S., Böhmer, M., Nishimura, N., … Schroeder, J. I. (2011). Chemical Genetics Reveals Negative Regulation of Abscisic Acid Signaling by a Plant Immune Response Pathway. Current Biology, 21(11), 990-997. doi:10.1016/j.cub.2011.04.045Waadt, R., Hitomi, K., Nishimura, N., Hitomi, C., Adams, S. R., Getzoff, E. D., & Schroeder, J. I. (2014). FRET-based reporters for the direct visualization of abscisic acid concentration changes and distribution in Arabidopsis. eLife, 3. doi:10.7554/elife.01739Jones, A. M., Danielson, J. Å., ManojKumar, S. N., Lanquar, V., Grossmann, G., & Frommer, W. B. (2014). Abscisic acid dynamics in roots detected with genetically encoded FRET sensors. eLife, 3. doi:10.7554/elife.01741Zhao, Y., Xing, L., Wang, X., Hou, Y.-J., Gao, J., Wang, P., … Zhu, J.-K. (2014). The ABA Receptor PYL8 Promotes Lateral Root Growth by Enhancing MYB77-Dependent Transcription of Auxin-Responsive Genes. Science Signaling, 7(328), ra53-ra53. doi:10.1126/scisignal.2005051Peirats-Llobet, M., Han, S.-K., Gonzalez-Guzman, M., Jeong, C. 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Deep learning-based lesion subtyping and prediction of clinical outcomes in COVID-19 pneumonia using chest CT

The main objective of this work is to develop and evaluate an artificial intelligence system based on deep learning capable of automatically identifying, quantifying, and characterizing COVID-19 pneumonia patterns in order to assess disease severity and predict clinical outcomes, and to compare the prediction performance with respect to human reader severity assessment and whole lung radiomics. We propose a deep learning based scheme to automatically segment the different lesion subtypes in nonenhanced CT scans. The automatic lesion quantification was used to predict clinical outcomes. The proposed technique has been independently tested in a multicentric cohort of 103 patients, retrospectively collected between March and July of 2020. Segmentation of lesion subtypes was evaluated using both overlapping (Dice) and distance-based (Hausdorff and average surface) metrics, while the proposed system to predict clinically relevant outcomes was assessed using the area under the curve (AUC). Additionally, other metrics including sensitivity, specificity, positive predictive value and negative predictive value were estimated. 95% confidence intervals were properly calculated. The agreement between the automatic estimate of parenchymal damage (%) and the radiologists' severity scoring was strong, with a Spearman correlation coefficient (R) of 0.83. The automatic quantification of lesion subtypes was able to predict patient mortality, admission to the Intensive Care Units (ICU) and need for mechanical ventilation with an AUC of 0.87, 0.73 and 0.68 respectively. The proposed artificial intelligence system enabled a better prediction of those clinically relevant outcomes when compared to the radiologists' interpretation and to whole lung radiomics. In conclusion, deep learning lesion subtyping in COVID-19 pneumonia from noncontrast chest CT enables quantitative assessment of disease severity and better prediction of clinical outcomes with respect to whole lung radiomics or radiologists' severity score

Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes

BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P = 0.98). There were no significant between-group differences in rates of acute pancreatitis (P = 0.07) or pancreatic cancer (P = 0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events

Consenso de expertos sobre el uso de alemtuzumab en la práctica clínica diaria en España

Introducción: Alemtuzumab es un fármaco de alta eficacia aprobado por la Agencia Europea de Medicamentos como tratamiento modificador de la enfermedad en pacientes con esclerosis múltiple remitente recurrente. Objetivo: Elaborar un documento de consenso sobre el manejo de alemtuzumab en la práctica clínica habitual, que sea de aplicación en el ámbito español. Desarrollo: Un grupo de expertos en esclerosis múltiple revisó las publicaciones disponibles hasta diciembre de 2017, de tratamiento con alemtuzumab y esclerosis múltiple. Se incluyeron trabajos sobre eficacia, efectividad y seguridad, despistaje de infecciones y vacunación, administración y monitorización. La propuesta inicial de recomendaciones fue desarrollada por un grupo coordinador con base en la evidencia disponible y en su experiencia clínica. El proceso de consenso se llevó a cabo en 2 etapas; se estableció como porcentaje inicial de acuerdo grupal el 80%. El documento final con todas las recomendaciones acordadas por el grupo de trabajo se sometió a revisión externa y los comentarios recibidos fueron considerados por el grupo coordinador. Conclusiones: El documento aportado pretende ser una herramienta útil para facilitar el manejo del fármaco en condiciones de práctica clínica habitual.Introduction: Alemtuzumab is a highly effective drug approved by the European Medicines Agency as a disease-modifying drug for the treatment of relapsing-remitting multiple sclerosis. Objective: A consensus document was drafted on the management of alemtuzumab in routine clinical practice in Spain. Development: A group of multiple sclerosis specialists reviewed articles addressing treatment with alemtuzumab in patients with multiple sclerosis and published before December 2017. The included studies assessed the drug's efficacy, effectiveness, and safety; screening for infections and vaccination; and administration and monitoring aspects. The initial proposed recommendations were developed by a coordinating group and based on the available evidence and their clinical experience. The consensus process was carried out in 2 stages, with the initial threshold percentage for group agreement established at 80%. The final document with all the recommendations agreed by the working group was submitted for external review and the comments received were considered by the coordinating group. Conclusion: The present document is intended to be used as a tool for optimising the management of alemtuzumab in routine clinical practice

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac